Manufacturing of Parenteral Preparations (Injections, Large Volume Parenterals, Small Volume Parenterals)

In this article we will discuss about manufacturing process. Read: Documentations, Requirements and other formalities to start parenteral dosage form manufacturing company.  

Parenteral Preparations are the preparations used administration by injections, infusions or implementations into body and directly injected into veins, muscles, under the skin or more specialized tissue such as spinal cord. These are sterile and pyrogen free liquids or solid dosage forms and may contain one or more active ingredients. Parenteral preparations are packed into either single dose or multi dose container.

Technical Staff:

• Manufacturing Chemist
• Analytical Chemist
• Quality Assurance Manager
• Production Supervisors

Non Technical Staff:

• Machine Operators
• Helpers

Parenteral preparations are in two forms:

• Liquid Parenateral Preparations
• Dry Powder Parenteral Preparation

Both type of preparation follow different type of procedure for preparing parenterals.

Types of parenteral Preparations

• Single Dose Parenterals
• Multiple Dose Parenterals

Section Required:

For Dry Injection:

• Sterile Raw Material Section
• Washing Section
• Terminal Sterilization Section
• Autoclave Sterilization Section
• Filling Section
• Capping and Sealing Section
• Labeling and Packaging Section 

For Liquid Injections:

• Warehouse
• Washing Section
• General Production Section
• Weighing, mixing and Transfer Section
• Sterilization Section
• Filling Section
• Capping and Sealing Section
• Labeling and Packaging Section

Parenteral Preparations require sterile pyrogen free atmosphere. Procedure involved in parenteral manufacturing:

For Dry Injections:

• Dispensing of Raw Material, API and Packaging Material
• Raw material and API ware-house should maintain aseptic area
• Washing, drying and Sterilization of Vials, Rubber stoppers, cap and sealing material
• Vials are sterilized and pyrozen free by means of Terminal at temperature more than 300 degree.
• Rubber cap and heat sensitive material is sterilized through Autoclave
• If raw material is not sterilized, material is sterilized through Autoclave
• After Sterilization, Vials are filling with sterilized raw material. Continuous inspection and documentation is essential.
• After filling vials go for capping and sealing.
• Then labeling and Packaging is conducted

For Liquid Parenteral Products:

• Dispensing of Raw, API and Packaging material
• Raw material and API ware-house should maintain aseptic area
• Washing, drying and Sterilization of Vials, Rubber stoppers, cap and sealing material
• Vials are sterilized and pyrozen free by means of Terminal at temperature more than 300 degree.
• Rubber cap and heat sensitive material is sterilized through Autoclave
• Preparation of Vehicle or solution
• Mix API and other raw material in above prepared preparation
• Filtration of whole solution for sterilization
• Filling
• Sealing
• Packaging
• Storage

Equipments and Machinery:

• Storage equipments for ampoules, Ampoules and Closures
• Washing and Drying Equipments
• Dust proof storage equipment including cold storage and refrigerator
• Water Still
• Mixing and Preparation Containers and Tanks
• Mixing Equipments
• Filtration Equipments
• Hot air sterilizer
• Benches and tables
• Bacteriological Filters
• Laminar Flow work station

Essential Steps:

• Products shall be released only after complete filling and testing. 
• Result of the tests relating to sterility, pyrogens, and Bacterial endotoxins shall be maintained in the analytical records. 
• Validation details and simulation trail records shall be maintained separately,
• Records of environmental monitoring like temperature, humidity, microbilogical data, etc. shall be maintained. Records of periodic servicing of HEPA filters, sterilizers and other periodic maintenance of facilities and equipment carried out also be maintained. 
• Separate facilities shall be provided for filling-cum-sealing of Small Volume Parenterals in glass containers and/or plastic containers, 
• It is advisable to provide separate facilities for manufacture of Large Volume Parenterals in glass containers and / or plastic containers. 
• For manufacture of Large Volume Parenterals in plastic containers, it is advisable to install automatic (with all operations) Form–Fill-Seal machines having one continuous operation.

Specific Requirements in Brief Only: (Ref: Schedule M) For complete information: Download Schedule M here:

1. General Specifications:

General Sterile products, being very critical and sensitive in nature, a very high degree of precautions, prevention and preparations and needed. Dampness, dirt and darkness are to be avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the prescribed standards especially in the matter of supply of water, air, active materials and in the maintenance of hygienic environment.

2. Building and Civil Works:

• Building should be constructed to avoid any cracks
• Location should avoid contamination and leakage
• All sections and departments shall be clearly separated from each other.
• Walls, floors and ceiling should be impervious, non-shedding, non-flaking and non-cracking. Flooring should be unbroken and provided with a cove both at the junction between the wall and the floor as well as the wall and ceiling. Walls shall be flat, and ledges and recesses shall be avoided. Wherever other surfaces join the wall (e,g, sterilizers, electric sockets, gas points etc.) these shall flush the walls. Walls shall be provided with a cove at the joint between the ceiling and floor
• Change rooms with entrance shall have air locks and separate exit space from the aseptic area.
• Material transfer between aseptic areas and outside shall be through suitable airlocks or pass-boxes. Doors of such airlocks and pass-boxes shall have suitable interlocking arrangements.

3. Air Handling System (Central Air Conditioning):

Air Handling Units for sterile product manufacturing areas shall be different from those for other areas. Critical areas, such as the aseptic filling area, sterilized components unloading area and change room conforming to Grades B, C and D respectively shall have separate air handling units. The filter configuration in the air handling system shall be suitably designed to achieve the Grade of air which shall be achieved by providing laminar air flow work stations with suitable HEPA filters or isolator technology

4. Environmental Monitoring:

All environmental parameters listed shall be verified and established at the time of installation and thereafter monitored at periodic intervals.

5. Garments:

This section covers garments required for use by personnel working only in aseptic area. Outdoor clothing shall not be brought into the sterile areas. Only clean, sterilized and protective garments shall be used at each work session where aseptic filtration and filling operations are undertaken and at each work shift for products intended to be sterilized, post-filling. The mask and gloves shall be changed at every work session in both instances.

6. Sanitation:

There shall be written procedures for the sanitation of sterile processing facilities. Employees carrying out sanitation of aseptic areas shall be trained specifically for this purpose.

7. Equipment:

The special equipment required for manufacturing sterile products includes component washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labeling machines, vacuum testing chambers, inspection machines, lyophilisers, pressure vessels etc. suitable and fully integrated washing sterilizing filling lines may be provided, depending upon the type and volume of activity.

8. Water System:

Potable water meeting microbiological specification of not more than 500 cfu/ml and indicating absence of individual pathogenic microorganisms, Escherichia coli, Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be used for the preparation of purified water

9. Manufacturing Process:

Manufacturing of sterile products shall required defined conditions and environment.

10. Form-Fill-Seal Technology or Blow, Fill-Seal Technology:

Form-Fill-Seal units are specially built automated machines in which through one continuous operation, containers are formed from thermoplastic granules, filled and then sealed. Blow, fill-seal units are machines in which containers are moulded / blown (pre-formed) in separate clean rooms, by non-continuous operations.

11. Product Container and Closures:

All containers and closures intended for use shall comply with the pharmacopoeial and other specified requirements.

12. Documentation:

The manufacturing records relating to manufacture of sterile products shall indicate the following details:

• Serial number of the Batch Manufacturing Record. 
• Name of the product 
• Reference to Master Formula Record. 
• Batch/Lot number 
• Batch/Lot size. 
• Date of commencement of manufacture and date of completion of manufacture. 
• Date of manufacture and assigned date of expiry. 
• Date of each step in manufacturing. 
• Names of all ingredients with the grade given by the quality control department. 
• Quality of all ingredients. 
• Control reference numbers for all ingredients. 
• Time and duration of blending, mixing, etc. whenever applicable. 
• PH of solution whenever applicable. 
• Filter integrity testing records 
• Temperature and humidity records whenever applicable 
• Records of plate-counts whenever applicable. 
• Results of pyrogen and/or bacterial endotoxin & toxicity. 
• Results of weight or volume of drug filled in containers. 
• Bulk sterility in case of aseptically filled products. 
• Leak test records. 
• Inspection records. 
• Sterilization records including autoclave leakage test records, load details, date, duration, temperature, pressure, etc. 
• Container washing records. 
• Total number of containers filled. 
• Total numbers of containers rejected at each stage 
• Theoretical yield, permissible yield, actual yield and variation thereof. 
• Clarification for variation in yield beyond permissible yield. 
• Reference numbers of relevant analytical reports. 
• Details of reprocessing, if any. 
• Name of all operators carrying out different activities. 
• Environmental monitoring records. 
• Specimens of printed packaging materials. 
• Records of destruction of rejected containers printed packaging and testing.
• Signature of competent technical staff responsible for manufacture and testing.